During the past decade, the relationship between monoamine uptake and a variety of diseases and conditions has been appreciated and investigated. For example, the hydrochloride salt of fluoxetine (dlN-methyl-3-[4-(trifluoromethyl)phenoxy]-3-phenylpropylamine) is a selective serotonin (5-hydroxytryptamine) uptake inhibitor. Fluoxetine hydrochloride is marketed under the trademark PROZAC.RTM. for the treatment of depression. This compound is among many taught in U.S. Pat. Nos. 4,018,895, 4,194,009, and 4,314,081 as being potent, selective blockers of serotonin uptake.
Fluoxetine is a racemate of the two enantiomeric forms. The biological and pharmacological activity of each enantiomer has been found to be essentially the same; see, Robertson et al., J. Med. Chem., 31, 1412 (1988) and references cited therein.
Norfluoxetine [3-(4-trifluoromethylphenoxy)3-phenylpropylamine] is a metabolite of fluoxetine and is known to block monoamine uptake, especially serotonin. See U.S. Pat. No. 4,313,896. Norfluoxetine has only been evaluated as the racemate, and since it is a metabolite of fluoxetine, it is believed that this compound contributes in part to the biological activity seen upon administration of fluoxetine. Since the eudismic ratio for fluoxetine, i.e., the ratio of affinities or activities of its two enantiomers, is approximately unity, conventional wisdom would suggest that the individual enantiomers of norfluoxetine would similarly have equivalent activities. We have unexpectedly discovered that the (S)-enantiomer of norfluoxetine is substantially more active than its (R)-optical antipode.